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Genes that made 1918 flu lethal isolated

15 January 2009

Researchers have identified a set of three genes that helped underpin
the extraordinary virulence of the 1918 virus — a virus that killed
between 20 and 50 million people in history’s most devastating outbreak
of infectious disease. The study was published in the Proceedings of the
National Academy of Sciences.

A team led by University of Wisconsin-Madison virologists Yoshihiro
Kawaoka and Tokiko Watanabe identifies genes that gave the 1918 virus
the capacity to reproduce in lung tissue, a hallmark of the pathogen
that claimed more lives than all the battles of World War I combined.

“Conventional flu viruses replicate mainly in the upper respiratory
tract: the mouth, nose and throat. The 1918 virus replicates in the
upper respiratory tract, but also in the lungs,” causing primary
pneumonia among its victims, says Kawaoka, an internationally recognized
expert on influenza and a professor of pathobiological sciences in the
UW-Madison School of Veterinary Medicine. “We wanted to know why the
1918 flu caused severe pneumonia.”

Autopsies of 1918 flu victims often revealed fluid-filled lungs
severely damaged by massive haemorrhaging. Scientists assumed that the
ability of the virus to take over the lungs is associated with the
pathogen’s high level of virulence, but the genes that conferred that
ability were unknown.

Discovery of the complex and its role in orchestrating infection in
the lungs is important because it could provide a way to quickly
identify the potential virulence factors in new pandemic strains of
influenza, Kawaoka says. The complex could also become a target for a
new class of antiviral drugs, which is urgently needed as vaccines are
unlikely to be produced fast enough at the outset of a pandemic to blunt
its spread.

To find the gene or genes that enabled the virus to invade the lungs,
Kawaoka and his group blended genetic elements from the 1918 flu virus
with those of a currently circulating avian influenza virus and tested
the variants on ferrets, an animal that mimics human flu infection.

For the most part, substituting single genes from the 1918 virus onto
the template of a much more benign contemporary virus yielded agents
that could only replicate in the upper respiratory tract. One exception,
however, included a complex of three genes that, acting in concert with
another key gene, allowed the virus to efficiently colonize lung cells
and make RNA polymerase, a protein necessary for the virus to reproduce.

“The RNA polymerase is used to make new copies of the virus,” Kawaoka
explains. Without the protein, the virus is unable to make new virus
particles and spread infection to nearby cells.
In the late 1990s, scientists were able to recover genes from the 1918
virus by looking in the preserved lung tissue of some of the pandemic’s
victims. Using the relic genes, Kawaoka’s group was able to generate
viruses that carry different combinations of the 1918 virus and modern
seasonal influenza virus.

When tested, most of the hybrid viruses only infected the nasal
passages of ferrets and didn’t cause pneumonia. But one did infect the
lungs, and it carried the RNA polymerase genes from the 1918 virus that
allowed the virus to make the key step of synthesizing its proteins.

In 2004, Kawaoka and his team identified another key gene from the
1918 virus that enhanced the pathogen’s virulence in mice. That gene
makes hemagglutinin, a protein found on the surface of the virus and
that confers on viral particles the ability to attach to host cells.
“Here, I think we are talking about another mechanism,” Kawaoka says.
The RNA polymerase is used to make copies of the virus once it has
entered a host cell. The role of hemagglutinin is to help the virus gain
access to cells.

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